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A versatile mouse that can teach us about life, diseases and drugs

Scientists from the BBSRC funded Babraham Institute in Cambridge have created a mouse that expresses a fluorescing ‘biosensor’, allowing many life and disease processes and the effects of drugs to be tracked and evaluated in real time and in three dimensions.

This biosensor mimics the action of a target molecule, a protein known as ‘Rac’, which drives cell movement during development, inflammation and wound repair, but also in cancer. Rac behaves like a switch, oscillating on the molecular level between two states – active or inactive. When Rac is active, the biosensor picks up biochemical cues and glows yellow. When Rac is inactive the biosensor glows blue.

Using sophisticated imaging techniques, it is possible to follow Rac activation in any organ at any time, or watch moment-by-moment oscillations of Rac activity within cells as they move. This technology has been used to monitor Rac activity in many organs in response to drug treatment.

The biosensor is a single molecule probe named ‘Raichu-Rac’ and was invented by Japanese scientist Professor Miki Matsuda in 2002.

Although many researchers have used Raichu-Rac since 2002, this is the first time a mouse has been genetically modified successfully in a targeted way that allows the biosensor to be expressed in any organ of choice or throughout the body, as required, without any effect on the mouse. One use of the mouse is in monitoring cancer development, but it can also easily be adapted to study other diseases by crossing it with relevant disease models. Equally it can be used in examining normal cell and tissue function.

Babraham Institute Group Leader, Dr Heidi Welch – the creator of the mouse – uses it to study the movement of immune cells, known as neutrophils that patrol the body to ensure immune defence against bacterial and fungal infections. Its use in cancer research was established in close collaboration with colleagues from the Beatson Institute for Cancer Research in Glasgow, including Dr Paul Timpson who recently moved to the Garvan Institute of Medical Research in Sydney, Australia. The study, now online, has been published in the open access journal Cell Reports.

“The great thing about this mouse is its versatility and potential for looking at a broad range of life processes, diseases and molecular targets,” said Dr Welch. “It allows us to watch and map, in real time, parts of a cell or organ where Rac is active. In cancer, for example, a lot of biosensor activity indicates an aggressive tumour in the process of spreading,” said Dr Timpson. “You can literally watch parts of a tumour switch colour as a drug hits its target, and then monitor how the effect of the drug wanes over time” said Dr Timpson”. Drug companies need to know these details - specifically how much, how often and how long to administer drugs.”

Dr Heidi Welch views the biosensor mouse mostly as a tool that will help other scientists to understand Rac biology and work out how to stop cancer cells from moving. “The credit must go to Professor Miki Matsuda, the genius who invented the biosensor in the first place 12 years ago,” she said. “He made his discovery freely available to the scientific community, and has been very open about his findings since. Miki Matsuda was super-helpful in suggesting the expression levels we should be looking for, and in recommending the exact biosensor we should use, out of many he developed. He was superb.”According to Dr Welch, competition is growing rapidly in this area, with Matsuda himself making biosensor mice for a variety of target molecules.

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